14,15-cyclopropano steroids of the 19-norandrostane series, method for the production thereof and pharmaceutical preparations containing said compounds

ABSTRACT

Described are new 14,15-cyclopropano steroids of the 19-norandrostane series of general formula (I) and their pharmaceutically acceptable salts, a process for their production and pharmaceutical preparations that contain these compounds. The compounds are distinguished by hormonal (gestagenic and/or androgenic) activity.

This application is a 371 of PCT/DE99/01795 filed on Jun. 18, 1999 whichclaims priority of DE 198 27 5226 of Jun. 11, 1998.

DESCRIPTION

The invention relates to new 14,15-cyclopropano steroids of the19-norandrostane series, their production and pharmaceuticalpreparations that contain these compounds.

14,15-Cyclopropano steroids of the 19-norandrostane series of generalformula I

as described.

In general formula I, R₁ is a hydrogen atom or an alkyl radical with 1-9carbon atoms,

R₂ stands for a hydrogen atom or a methyl group,

R₃ and R₄, independently of one another, stand for a hydrogen atom, fora hydroxy group, for an acyloxy group —O—CO—R₅ with R₅ standing for 1-10carbon atoms, for a carbamoyloxy group O—CO—NHR₆, with R₆ standing for ahydrogen atom, an alkyl or aryl radical with 1-5 carbon atoms in eachcase, for a sulfamoyloxy group —O—SO₂—NR₇R₈ with R₇ and R₈,independently of one another, in each case standing for a hydrogen atom,an alkyl group with 1 to 5 carbon atoms or together with the nitrogenatom for a pyrrolidino, piperidino or morpholino group, for a grouping—CH₂R₉ with R₉ standing for a hydroxy group, an alkyloxy group with 1-5carbon atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyanogroup or for a grouping —SR₁₀ with R₁₀ standing for an alkyl group with1-5 carbon atoms,

or R₃ and R₄ together stand for an oxo group,

or R₃ and R₄, with the inclusion of C-17, form a spirooxirane or a2,2-dimethyl-1,3-dioxolane,

and the 14,15-cyclopropane ring is arranged either in α- or β-position,whereby R₂ is an α-position, if the cyclopropane ring is in β-positionand vice versa.

The compounds according to the invention, the new 14,15-cyclopropanosteroids of the 19-norandrostane series, have not yet been described.Their biological action is still unknown.

The object of this invention is to make available 14,15-cyclopropanosteroids of the 19-norandrostane series of general formula

and their pharmaceutically acceptable salts as well as a process fortheir production.

Another object is to make available pharmaceutical preparations thatcontain at least one compound of general formula I or theirpharmaceutically acceptable salts.

In general formula I

R₁ is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,

R₂ stands for a hydrogen atom or a methyl group,

R₃ and R₄, independently of one another, stand for a hydrogen atom, fora hydroxy group, for an acyloxy group —O—CO—R₅ with R₅ standing for 1-10carbon atoms, for a carbamoyloxy group —O—CO—NHR₆, with R₆ standing fora hydrogen atom, an alkyl or aryl radical with 1-5 carbon atoms in eachcase, for a sulfamoyloxy group —O—SO₂—NR₇R₈ with R₇ and R₈,independently of one another, in each case standing for a hydrogen atom,an alkyl group with 1 to 5 carbon atoms or together with the nitrogenatom for a pyrrolidino, piperidino or morpholino group, for a grouping—CH₂R₉ with R₉ standing for a hydroxy group, an alkyloxy group with 1-5Catoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano groupor for a grouping —SR₁₀ with R₁₀ standing for an alkyl group with 1-5carbon atoms,

or R₃ and R₄ together stand for an oxo group,

or R₃ and R₄, with the inclusion of C-17, form a spirooxirane or a2,2-dimethyl-1,3-dioxolane,

and the 14,15-cyclopropane ring is arranged either in α- or β-position,whereby R₂ is in α-position, if the cyclopropane ring is in β-positionand vice versa.

Most preferred are

17β-Hydroxy-14α,15α-methylenestr-4-en-3-one (J 1129),

17α-hydroxy-14α,15α-methylenestr-4-en-3-one,

17β-hydroxy-15β-methyl-14α,15α-methylenestr-4-en-3-one,

17β-hydroxy-15α-methyl-14β,15β-methylenestr-4-en-3-one,

17β-hydroxy-17α-hydroxymethyl-14α,15α-methylenestr-4-en-3-one,

17α-methoxy-17β-methyloxymethyl-14α,15α-methylenestr-4-en-3-one,

17β-hydroxy-7α-methyl-14α,15α-methylenestr-4-en-3-one,

17,20-isopropylidenedioxy-14α,15α-methylene-19,21-bis-nor-17α-pregn-4-en-3-one,

3-oxo-14α,15α-methylenestr-4-en-17β-yl-sulfamate,

3-oxo-14α,15α-methylenestr-4-en-17β-yl-n-butanoate,

17β-hydroxy-17α-methyloxymethyl-14β,15β-methylenestr-4-en-3-one (J1222),

17α-ethylthiomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one (J1411),

17α-chloromethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one (J 1364),

17α-azidomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one (J 1370),

17α-bromomethyl-17β-hydroxy-14β,15β-ethylenestr-4-en-3-one (J 1424),

17β-hydroxy-17α-rhodanomethyl-14β,15β-methylenestr-4-en-3-one (J 1470),

17α-cyanomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one (J 1517).

The invention also relates to a process for the production of thecompounds according to general formula I and their pharmaceuticallyacceptable salts, which is characterized in that a compound of generalformula II

in which R₁, R₂, R₃ and R₅ have the above-indicated meaning, is producedby enol ether cleavage in a way that is known in the art.

The enol ether cleavage is performed by the action of strong acids, suchas sulfuric acid, hydrochloric acid or organic sulfonic acids, on thecompounds of general formula I that are dissolved in a suitable organicsolvent.

Subjects of this invention are pharmaceutical substances for oral,rectal, subcutaneous, intravenous or intramuscular use, which togetherwith the commonly used vehicles and diluents can contain at least onecompound of general formula I or its acid addition salts as an activeingredient.

Pharmaceutical preparations of the invention are produced with thecommonly used solid or liquid vehicles and/or diluents and the generallycommonly used adjuvants corresponding to the desired type ofadministration in a suitable dosage and in a way that is known in theart. In the case of a preferred oral form for dispensing, preferablytablets, film tablets, coated tablets, capsules, pills, powders,solutions or suspensions are also prepared as a depot form.

In addition, parenteral dosage forms such as injection solutions or elsesuppositories are also considered.

Dosage forms as tablets can be obtained by, for example, mixing theactive ingredient with known adjuvants, such as dextrose, sugar,sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starchor alginic acid, binders such as starch or gelatin, lubricants such asmagnesium stearate or talc and/or agents that can achieve a depoteffect, such as carboxylpolymethylene, carboxymethyl cellulose,cellulose acetate phthalate or polyvinyl acetate. The tablets can alsoconsist of several layers.

Coated tablets can be prepared analogously by coating cores that areproduced analogously to the tablets with agents that are commonly usedin tablet coatings, for example polyvinylpyrrolidone or shellac, gumarabic, talc, titanium dioxide or sugar. In this case, the coated tabletshell can also consist of several layers, whereby for example, theabove-mentioned adjuvants are used.

To improve the taste, the solutions or suspensions with the activeingredient according to the invention can be mixed with substances suchas saccharin, cyclamate or sugar and/or with flavoring substances, suchas vanillin or orange extract. In addition, they can be mixed withsuspension adjuvants, such as sodium carboxymethyl cellulose orpreservatives such as p-hydroxybenzoic acid.

The preparation of capsules can be carried out by mixing apharmaceutical substance with vehicles such as lactose or sorbitol,which then are introduced into the capsules.

The production of suppositories is preferably carried out by mixing theactive ingredient with suitable vehicles, such as neutral fats orpolyethylene glycols or derivatives thereof.

In addition, the pharmaceutical preparation forms can be percutaneouspreparation forms, e.g., transdermal therapeutic systems (TS) or gels,sprays or ointments or intranasal preparation forms such as nose sprayor nose drops.

The 14,15-cyclopropano steroids of the 19-norandrostane series ofgeneral formula I according to the invention are hormonal (gestagenic-and/or androgenic-acting) compounds.

Thus, for example, the compound of general formula I—in which R₁ and R₂in each case represent a hydrogen atom, R₃ means an α-positionmethyloxymethyl group and R⁴ means a β-position hydroxy group and thecyclopropano group is arrange dinβ-position—17β-hydroxy-17α-methyloxymethyl-14β,15β-methylenestr-4-en-3-one(J 1222), is just as effective in the pregnancy maintenance test in miceas the gestagen norethisterone acetate that is used worldwide for oralcontraception.

Another example is the compound of general formula I—in which R₁ and R₂in each case represent a hydrogen atom, R₃ represents an α-positionhydrogen atom, R₄ stands for a β-position hydroxy group, and thecyclopropane ring is inα-position—17β-hydroxy-14,α,15α-methylenestr-4-en-3-one (J 1129), whichin the same test has an approximately 50-fold stronger gestagenic actionin comparison to the reference substance norethisterone acetate.

While the substance17β-hydroxy-17α-methyloxymethyl-14β,15β-methylenestr-4-en-3-one (J 1222)with 52±4% binds to the progesterone receptor of the rabbit uterus(reference substance: progesterone), there is virtually no affinity tothe androgen receptor of the rat prostate (reference substance:17β-hydroxy-17α-methyl-estra-4,9,11-trien-3-one; R 1881).

17β-Hydroxy-14α,15α-methylenestr-4-en-3-one (J 1129), however, shows a59±7% binding to the androgen receptor, which corresponds to the bindingaffinity of the naturally occurring male sex hormone testosterone, and a42±5% binding to the progesterone receptor.

Another example is the compound of general formula I—in which R₁ and R₂in each case represent a hydrogen atom, R₃ means an α-positionchloromethyl group, R4 stands for a β-position hydroxy group, and thecyclopropane ring is inβ-position—17α-chloromethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one(Code J 1364), which binds with 710±80% to the progesterone receptor ofthe rabbit uterus (reference substance: progesterone).

In the compounds of general formula I according to the invention, thesetest results open up many possibilities for birth control in men andwomen, hormone replacement therapy in men and women, or the treatment orhormonally produced diseases in men and women, such as, for example,endometriosis, breast cancer or hypogonadism.

The compounds of general formula I according to the invention are to beexplained in more detail in the examples below, but are not limitedthereto.

EXAMPLE 117α-Ethylthiomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one

500 mg of17(S)-3-methoxy-17-spiroepoxy-14β,15β-methylenestra-2,5(10)-diene isheated to 80° C. in 10 ml of DMSO with 270 mg of sodium ethyl thiolatefor 4 hours. It is poured into aqueous sodium chloride solution, thebrown precipitate is suctioned off and washed neutral. It is dissolvedwith actone from the frit, and the solution is concentrated byevaporation under a vacuum. A brown oil, which is purified bypreparative layer chromatography on silica gel PF_(254+366 nm) (MERCKAG) with the mobile solvent mixture of toluene/acetone 50:1, remains.

225 mg of17α-ethylthiomethyl-3-methoxy-17β-hydroxy-14β,15β-methylenestra-2,5(10-dieneis reacted in 3.0 ml of dimethylformamide with 0.3 ml of HCl(concentrated) within 1 hour. After aqueous NaHCO₃ solution is added, itis neutralized, extracted with CH₂Cl₂, the organic phase is washedneutral, dried on sodium sulfate and evaporated under a vacuum. An oilis obtained that is purified by preparative layer chromatography onsilica gel PF_(254+366 nm) (MERCK AG) with the mobile solvent mixture oftoluene/acetone 10:1.

After recrystallization from ethanol,17α-ethylthiomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one isobtained.

Flash point: 92-98° C.; ¹H-NMR (CDCl₃/TMS): 0.47 (2H, m, 14β,15β-CH₂),1.07 (3H, s, H₁₈); 1.28 (3H, t, SCH₂CH₃), 2.52 (2H, q, 14.7 Hz, 7.5 Hz,SCH₂), 2.62 and 2.78 (2H, 2d, 12.6 Hz, 17αCH₂S—); 2.89 (1H, s, OH), 5.81(1H, s, H₄); after TAI: 0.55 (2H, m, 14β,15β-CH₂), 1.21 (3H, t,SCH₂CH₃), 1.34 (3H, s, H₁₈), 2.46 (2H, q, 7.5 Hz, 14.7 Hz, SCH₂), 2.82and 3.00 (2H, 2d, 13.2 Hz, 17α CH₂S—); 5.81 (1H, s, H₄); 8.21 (s, NHCO)ppm.

EXAMPLE 2 17α-Chloromethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one(J 1364)

625 mg of17(S)-3-methoxy-17-spiroepoxy-14β,15β-methylenestra-2,5(10)-diene isdissolved in 10 ml of DMF and mixed with 1 ml of HCl (concentrated atroom temperature. It is stirred for 1.5 hours, poured into ice water,the deposited precipitate is suctioned off, washed neutral andair-dried. The crude product is purified by preparative layerchromatography on silica gel PF_(254+366 nm) (MERCK AG) with the mobilesolvent mixture of toluene/acetone 15:1.

After recrystallization from acetone,17α-chloromethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one isobtained.

Flash point: 177-179° C.; α_(D)=+67° (CHCl₃), ¹H-NMR (CDCl₃/TMS+TAI);0.48 (2H, m, 14β,15β-CH₂), 1.34 (3H, s, H₁₈); 2.15 (1H, s, OH), 3.56 and3.67 (2H, 2d, 8.4 Hz, 17α-CH₂Cl); 5.79 (1H, s, H₄) ppm.

EXAMPLE 3 17α-Azidomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one

550 mg of17(S)-3-methoxy-17-spiroepoxy-14β,15β-methylenestra-2,5(10)-diene isheated to 100° C. in 35 ml of ethylene glycol with 2.6 g of sodium azidefor 6 hours. It is poured into ice water, extracted with CH₂Cl₂, washedneutral, dried on sodium sulfate, and the solution is concentrated byevaporation under a vacuum. The crude product is purified by preparativelayer chromatography on silica gel PF_(254+366 nm) (MERCK AG) with themobile solvent mixture of toluene/acetone 50:1). After recrystallizationfrom acetone,17α-azidomethyl-17β-hydroxy-14β,15β-methylenestra-2,5(10)-3-methyl etheris obtained as crystals with a melting point of 138-143° C.

285 mg of17α-azidomethyl-17β-hydroxy-3-methoxy-14β,15β-methylenestra-2,5(10)-dieneis reacted in 4 ml of dimethylformamide with 0.4 ml of HCl(concentrated) within 2 hours. After aqueous NaHCO₃ solution is added,it is neutralized, extracted with CH₂Cl₂, the organic phase is washedneutral, dried on sodium sulfate and evaporated under a vacuum. A yellowoil that is purified by preparative layer chromatography on silica gelPF_(254+366 nm) (MERCK AG) with the mobile solvent mixture oftoluene/acetone 20:1 is obtained.

After recrystallization from tert-butyl methyl ether/hexane,17α-azidomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one is obtained.

Flash point: 160-163° C.; α_(D)=+84° (CHCl₃), ¹H-NMR (CDCl₃/TMS); 0.54(2H, m, 14β,15β-CH₂), 1.28 (3H, s, H₁₈); 2.03 (1H, s, OH), 3.34 and 3.46(2H, 2d, 12.0 Hz, CH₂N₃), 5.81 (s, 1H, H₄) ppm.

EXAMPLE 417β-Hydroxy-17α-(methoxymethyl)-14β,15β-methylenestr-4-en-3-one (J 1222)

3.42 g of17α-(methoxymethyl)-3-methoxy-14β,15β-methylenestra-2,5(10)-dien-17β-olis suspended in 70 ml of MeOH and mixed with 3.4 ml of HCl (concentratedat room temperature. It is stirred for 2 hours, mixed with 50 ml ofwater and neutralized with aqueous bicarbonate solution. The depositedprecipitate is suctioned off, washed neutral and air-dried. Yield: 3.19g of crude product. Purification by column chromatography on silica gel(0.063-0.2 mm MERCK AG) with a toluene/acetone gradient.

After recrystallization from isopropanol, 2.4 g of17β-hydroxy-17α-(methoxymethyl)-14β,15β-methylenestr-4-en-3-one isobtained.

Flash point: 113-115° C. (isopropanol); α_(D)=+49° (CHCl₃), ¹H-NMR(CDCl₃/TMS); 0.47 (2H, m, 14β,15β-CH₂), 1.10 (3H, s, H₁₈); 2.71 (1H, s,OH), 3.17 and 3.44 (2H, 2d, 9.0 Hz, 17α-CH₂OCH₃); 3.33 (1H, s, OCH₃),5.81 (1H, s, H₄) ppm.

EXAMPLE 5 17β-Hydroxy-14α,15α-methylenestr-4-en-3-one (J 1129)

A solution that consists of 2 g of17β-hydroxy-14α,15α-methylenestr-5-en-3-one in 95 ml of acetone and 5 mlof 5% aqueous hydrochloric acid is stirred for 2.5 hours at roomtemperature. Then, 10 ml of saturated aqueous sodium bicarbonatesolution and 200 ml of water are added in succession. This solution isconcentrated by evaporation in a vacuum rotary evaporator, wherebycrystallization is used. The crystals are filtered off, dried, dissolvedin acetone and applied to a silica gel column (0.063-0.2 mm, Merck).Chromatography with cyclohexane ethyl acetate 7:3 (v/v) as an eluantyields 17β-hydroxy-14α,15α-methylenestr-4-en-3-one.

Flash point 168-170° C.; [α]_(D) ²⁰+67° (pyridine); ¹H-NMR(CDCl₃/TMS+TAI): 0.265 (1H, dd, 5.8 Hz, 3.2 Hz, 14α,15α-CH₂); 0.338 (1H,t, 7 Hz, 14α,15α-CH₂); 1.13 (3H, s, H₁₈); 4.58 (1H, dd, H_(17α)); 5.82(s, H₄); 8.41 (s, NH) ppm.

EXAMPLE 6 17α-Hydroxy-14α,15α-methylenestr-4-en-3-one

17α-Hydroxy-14α,15α-methylenestr-5-en-3-one is treated with hydrochloricacid in acetone analogously to Example 5, and the product is subjectedto chromatography, whereby 17α-hydroxy-14α,15α-methylenestr-04-en-3-oneis obtained.

¹H-NMR (CDCl₃/TMS+TAI); 0.39 (1H, dd, 7.2 Hz, 4.9 Hz, 14α,15α-CH₂); 0.67(1H, dd, 4.9 Hz, 2.8 Hz, 14α,15α-CH₂); 1.12 (3H, s, H₁₈); (4.96, 1H, d,6.1 Hz, H₁₇₈); 5.81 (s, H₄); 8.42 (s, NH) ppm.

EXAMPLE 7 17β-Hydroxy-17α-hydroxymethyl-14α,15α-methylenestr-4-en-3-one

17β-Hydroxy-17α-hydroxymethyl-14α,15α-methylenestr-5-en-3-one is treatedwith hydrochloric acid in acetone analogously to Example 5, and theproduct is subjected to chromatography, whereby17β-hydroxy-17α-hydroxymethyl-14α,15α-methylenestr-4-en-3-one isobtained.

¹H-NMR (CDCl₃TMS+TAI): 0.26 (1H, dd, 6.8 Hz, 2.0 Hz, 14α,15α-CH₂); 0.51(1H, t, 6.8 Hz, 14α,15α-CH₂); 1.26 (3H, s, H₁₈); 4.58, 4.93 (2H, AB,12.2 Hz, CH₂O); 5.82 (1H, t, 2.2 Hz, H₄); 8.44 (1H, s, NH); 8.52 (1H, s,NH) ppm.

EXAMPLE 8 17α-Methoxy-17β-methoxymethyl-14α,15α-methylenestr-4-en-3-one

17α-Methoxy-17β-methoxymethyl-14α,15α-methylenestr-5-en-3-one is treatedwith hydrochloric acid in acetone analogously to Example 5, and theproduct is subjected to chromatography, whereby17α-methoxy-17β-methoxymethyl-14α,15α-methylenestr-4-en-3-one isobtained.

¹H-NMR (CDCl₃/TMS): 0.18 (1H, m 14α,15α-CH₂); 0.954 (1H, t, 3.3 Hz,14α,15α-CH₂); 1.11 (3H, s, H₁₈); 3.15 (3H, s, OCH₃); 3.31 (3H, s, OCH₃);3.26, 3.52 (2H, AB, 11.2 Hz, CH₂O), 5.80 (1H, t, 1 Hz, H₄) ppm.

EXAMPLE 917,20-Isopropylidenedioxy-14α,15α-methylene-19,21-bis-nor-17α-pregn-4-en-3-one

17,20-Isopropylidenedioxy-14α,15α-methylene-19,21-bis-nor-17α-pregna-5-en-3-oneis treated with hydrochloric acid in acetone analogously to Example 5,and the product is subjected to chromatography, whereby17,20-isopropylidenedioxy-14α,15α-methylene-19,21-bis-nor-17α-pregn-4-en-3-oneis obtained.

¹H-NMR (CDCl₃/TMS): −0.27 (1H, m, 14α,15α-CH₂); 0.32 (t, 14α,15α-CH₂);1.14 (3H, s, H₁₈); 1.30 (3H, s, OCH₃); 1.37 (3H, s, OCH₃); 3.50, 4.07(2H, AB, 8.5 Hz, CH₂O), 5.81 (1H, t, 2.2 Hz, H₄) ppm.

EXAMPLE 10 17α-Bromomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one

666 mg of 17(S)-spiroepoxy-14β,15β-methylenestra-2,5(10)-diene-3-methylether is dissolved in 10 ml of DMF and mixed with 2.5 ml of HBR (48%) atroom temperature. It is stirred for 4 hours, poured into ice water, thedeposited precipitate is suctioned off, washed neutral and air-dried.The crude product is purified by preparative layer chromatography onsilica gel PF_(254+366 nm) (MERCK AG) with the mobile solvent mixture oftoluene/acetone 20:1.

After twice-repeated recrystallization from acetone, 324 mg of17α-bromomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one is obtained.

Flash point: 143 (dec.) ° C.; α_(D)=+68° (CHCl₃), ¹H-NMR (CDCl₃, ppm,TMS); 0.50 (m, 2H, 14β,15β-CH₂), 1.15 (s, 3H, H-18); 2.27 (s, 1H, OH),3.57 (t, 2H, J=10.2 Hz, H-17α-CH₂Br); 5.81 (s, 1H, H-4).

EXAMPLE 11 17β-Hydroxy-17α-rhodanomethyl-14β,15β-methylenestr-4-en-3-one

666 mg of 17(S)-spiroepoxy-14β,15β-methylenestra-2,5(10)-diene-3-methylether is dissolved in 10 ml of DMF and mixed with 2.5 ml of HBr (48%) atroom temperature. It is stirred for 4 hours, poured into ice water, thedeposited precipitate is suctioned off, washed neutral and air-dried.The crude product is purified by preparative layer chromatography onsilica gel PF_(254+366 nm) (MERCK AG) with the mobile solvent mixture oftoluene/acetone 20:1.

After recrystallization from ethyl acetate and MeOH that is repeatedthree times, 185 mg of17β-hydroxy-17α-rhodanomethyl-14β,15β-methylenestr-4-en-3-one isobtained.

Flash point: 168-173° C. (MeOH); α_(D)=+86° (CHCl₃), ¹H-NMR (CDCl₃, ppm,TMS); 0.53 (m, 2H, 14β,15β-CH₂), 1.11 (s, 3H, H-18); 1.98 (s, 1H, OH),3.21 (t, 2H, J=10.2 Hz, H-17α-CH₂SCN); 5.82 (s, 1H, H-4).

EXAMPLE 12 17α-Cyanomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one

624 mg of 17(S)-spiroepoxy-14β,15β-methylenestra-2,5(10)-diene-3-methylether is suspended in 15 ml of ethanol and stirred with 490 mg of sodiumcyanide at room temperature until conversion is completed. Then, it ispoured into ice water, it is suctioned off, washed neutral andair-dried. The crude product of17α-cyanomethyl-3-methoxy-14β,15β-methylenestra-2,5(10)-dien-17β-ol ispurified by preparative layer chromatography on silica gelPF_(254+366 nm) (MERCK AG) with the mobile solvent mixture oftoluene/acetone 20:1, dissolve din 10 ml of DMF and mixed with 0.5 ml ofHCl. After 2 hours, it is poured into ice water, the precipitate issuctioned off and purified by chromatography. The recrystallization of17α-cyanomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one is carriedout from acetone.

Flash point: 244-253° C.; α_(D)=+65° (CHCl₃), ¹H-NMR (CDCl₃/TMS); 0.56(m, 2H, 14β,15β-CH₂), 1.17 (s, 3H, H-18); 2.28 (s, 1H, OH), 2.3-2.5 (m,H-17α-CH₂CN); 5.82 (s, 1H, H-4).

What is claimed is:
 1. A compound of formula I

in which R₁ is a hydrogen atom or an alkyl radical with 1-9 carbonatoms, R₂ is a hydrogen atom or a methyl group, R₃ and R₄, independentlyof one another, stand for a a hydrogen atom, for a hydroxy group, for anacyloxy group —O—CO—R₅, with R₅ standing for an alkyl of 1-10 carbonatoms, for a carbamoyloxy group —O—CO—NHR₆, with R₆ standing for ahydrogen atom or an alkyl or aryl radical, for a sulfamoyloxy group—O—SO₂—NR₇R₈, with R₇ and R₈, independently of one another, in each casestanding for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms ortogether with the nitrogen atom for a pyrrolidino, piperidono ormorpholino group, for a grouping —CH₂R₉ with R₉ standing for a hydroxygroup, an alkyloxy group with 1-5 carbon atoms, a chlorine or bromineatom, an azido, nitrilo or thiocyano group or for a grouping —SR₁₀ withR₁₀ standing for an alkyl group with 1-5 carbon atoms, R₃ and R₄together stand for an oxo group, or R₃ and R₄, with C-17, form aspirooxirane or a 2,2-dimethyl-1,3-dioxolane group, or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, 17β-hydroxy-14α,15α-methylenstr-4-en-3-one or apharmaceutically acceptable salt thereof,17α-hydroxy-14α,15α-methylenestr-4-en-3-one or a pharmaceuticallyacceptable salt thereof,17β-hydroxy-15β-methyl-14α,15α-methylenstr-4-en-3-one or apharmaceutically acceptable salt thereof,17β-hydroxy-15α-methyl-14β,15β-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17β-hydroxy-17α-hydroxymethyl-14α,15α-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17α-methoxy-17β-methoxymethyl-14α,15α-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17β-hydroxy-7α-methyl-14α,15α-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17,20-isopropylidenedioxy-14α,15α-methylene-19,21-bis-nor-17α-pregn-4-en-3-oneor a pharmaceutically acceptable salt thereof,3-oxo-14α,15α-methylenstr-4-en-17β-yl-sulfamate or a pharmaceuticallyacceptable salt thereof,3-oxo-14α,15α-methylenestr-4-en-17β-yl-n-butanoate or a pharmaceuticallyacceptable salt thereof,17β-hydroxy-17α-methyloxymethyl-14β-,15β-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17α-ethylthiomethyl-17β-hydroxy-14β,15β-methylenestr-4-ene-3-one or apharmaceutically acceptable salt thereof,17α-chloromethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17α-azidomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17α-bromomethyl-17β-hydroxy-14β,15β-ethylenestr-4-en-3-one or apharmaceutically acceptable salt thereof,17β-hydroxy-17α-rhodanomethyl-14β,15β-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof or,17α-cyanomethyl-17β-hydroxy-14β,15β-methylenestr-4-en-3-one or apharmaceutically acceptable salt thereof.
 3. A process for theproduction of a compound according to claim 1 and its pharmaceuticallyacceptable salt comprising enol-ether cleaving a corresponding14,15-cyclopropano-enol ether of the general formula II,

in which R₁ is a hydrogen atom or an alkyl radical with 1-9 carbonatoms, R₂ is a hydrogen atom or a methyl group, R₃ and R₄, independentlyof one another, stand for a hydrogen atom for a hydroxy group, for aacyloxy group —O—CO—R₅ with R₅ standing for an alkyl of 1-10 carbonatoms, for a carbamoyloxyl group —O—CO—NHR₆, with R₆ standing for ahydrogen atom, or an alkyl or aryl radical, for a sulfamoyloxy group—O—SO₂—NR₇R₈, with R₇ and R₈, independently of one another, in each casestanding for a hydrogen atom, an alkyl group with 1-5 carbon atoms ortogether with the nitrogen atom for a pyrrolidino, piperidono ormorphilino group, for a grouping —CH₂R₉ with R₉ standing for a hydroxygroup, an alkyloxy group with 1-5 carbon atoms, a chlorine or bromineatom, an azido, nitrilo or thiocyano group or for a grouping —SR₁₀ withR₁₀ standing for an alkyl group with 1-5 carbon atoms, R₃ and R₄together stand for an oxo group, or R₃ and R₄, with C-17, form aspirooxirane or a 2,2-dimethyl-1,3-dioxolane group.
 4. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 5. A compound of formula I

in which R₁ is a hydrogen atom or an alkyl radical with 1-9 carbonatoms, R₂ is a hydrogen atom or a methyl group, R₃ and R₄, independentlyof one another, stand for a a hydrogen atom, for a hydroxy group, for anacyloxy group —O—CO—R₅, with R₅ standing for an alkyl of 1-10 carbonatoms, for a carbamoyloxy group —O—CO—NHR₆, with R₆ standing for ahydrogen atom or an alkyl radical, for a sulfamoyloxy group—O—SO₂—NR₇R₈, with R₇ and R₈, independently of one another, in each casestanding for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms ortogether with the nitrogen atom for a pyrrolidino, piperidono ormorpholino group, for a grouping —CH₂R₉ with R₉ standing for a hydroxygroup, an alkyloxy group with 1-5 carbon atoms, a chlorine or bromineatom, an azido, nitrilo or thiocyano group or for a grouping —SR₁₀ withR₁₀ standing for an alkyl group with 1-5 carbon atoms, R₃ and R₄together stand for an oxo group, or R₃ and R₄, with C-17, form aspirooxirane or a 2,2-dimethyl-1,3-dioxolane group, or apharmaceutically acceptable salt thereof.